Dental caries (tooth decay) is one of the most prevalent and costly infectious diseases in the United States affecting approximately 52% of children aged 5 to 9 years and approximately 85% adults 18 or older. Currently, the annual expenditures on dental services in the United States exceed $70 billion with the majority of these costs attributable to dental caries. Extensive research has demonstrated that dental caries is caused by the overgrowth of a group of cariogenic bacteria (i.e. Streptococcus mutans) that co-reside with over 400 other non-harmful/commensal microbial species in the dental plaque. The current anti-microbial strategies used to treat dental caries are not effective due to the nonspecific nature of these therapies. In this study, we propose a novel approach to selectively kill or inhibit the cariogenic bacteria within a dental plaque, thus achieving long-lasting therapeutic effects. We propose to use the "smart-bomb" technology to develop antimicrobial peptides specifically targeting S. mutans. In phase 1, we will identify the targeting peptides, construct target specific antimicrobial peptides, and test their efficacy with our well developed in vitro dental plaque systems. More specifically, the phase 1 goals are: 1. To obtain peptides that bind specifically to S. mutans. These peptides will be identified through 1) examining the known S. mutans-binding peptides such as CSP (competence stimulating peptide), 2) isolating small peptides produced and secreted by the cell cultures of S. mutans, 3) chemically synthesizing and testing small peptides identified through mining the S. mutans genome sequence. 2. To construct anti-S. mutans peptides by fusing the above targeting peptides with an antimicrobial defensin peptide (i.e. novispirin G10). The resulting fusion peptides will be tested for their ability to selectively kill S. mutans in liquid cultures or within multi species in vitro dental biofilms.